Poly(p-dioxanone) polymers having improved radiation resistance

ABSTRACT

A sterile surgical suture comprising an absorbable, radiation sterilizable, normally solid polymer comprising a copolyester that comprises repeating divalent units of the formulas: 
     (A) --O--CO--CH 2  --O--CH 2  CH 2  --, and 
     (B) --G--, and 
     (C) --O--CO--CHR--O-- m  Ph--O--CHR--CO--O-- 
     wherein G represents the residue after removal of the hydroxyl groups of a dihydric alcohol, wherein Ph represents 1,2-, 1,3-, or 1,4-phenylene or alkyl- or alkoxy-substituted phenylene, wherein m represents a number having a value of 0 or 1, wherein R represents hydrogen or lower alkyl, and wherein the divalent units (A), (B), and (C) are bonded to each other through ester groups contained in said units.

This application is a division of our copending application Ser. No.587,332, filed Mar. 7, 1984 now U.S. Pat. No. 4,546,152.

The invention relates to polymers made from p-dioxanone, and to thevaluable surgical products that can be made therefrom. The polymers haveenhanced radiation resistance and other valuable attributes.

BACKGROUND OF THE INVENTION

Synthetic absorbable polymers have been used to produce various surgicalproducts such as sutures, implants, prostheses, and the like, forseveral years. Illustrative U.S. Patents that disclose such polymers areU.S. Pat. Nos. 3,297,033, 3,044,942, 3,371,069, 3,531,561, 3,636,956, RE30,170, and 4,052,988.

Implantable surgical devices must be sterile prior to implanting in thebody. Sterilization of devices is usually accomplished by the use ofheat, ethylene oxide, or gamma radiation using a ⁶⁰ Co source. In manycases, the use of gamma radiation is the most convenient and mostcertain way to effect sterilization. However, all of the syntheticabsorbable polymers now in commercial use are degraded at least someextent by gamma radiation. Therefore, unless for some reason degradationof the polymer is desired (for instance, to accelerate the absorptionrate), the use of gamma radiation is ordinarily precluded for thepurpose of sterilizing the presently commercial synthetic absorbablepolymers.

This invention provides a new class or polymers that are absorbable andwhich can be sterilized by gamma radiation while still retaining adesirable level of physical and biological properties.

SUMMARY OF THE INVENTION

The polymers provided by the invention are derived from p-dioxanone, andcertain moieties that impart enhanced resistance to degradation by gammaradiation. The polymers of the invention are copolyesters that compriserepeating divalent units of the formulas:

(A) O--CO--CH₂ --O--CH₂ --CH₂, and

(B) G, and

(C) O--CO--(CHR-O--)_(m) --Ph--O--CHR--CO-O--

wherein G represents the residue after removal of the hydroxyl groups ofa dihydric alcohol, wherein Ph represents phenylene or alkyl- oralkoxy-substituted phenylene, and wherein m represents a number having avalue of 0 or 1, wherein each R individually represents hydrogen orlower alkyl, and wherein the divalent units (A), (B), and (C) are bondedto each other through ester groups formed by linking said units. Thesepolymers are useful in the production of surgical products such assutures, ligating clips, and the like.

The Prior Art

Kito et al., in Kogyo Kagaku Zasshi 1971, 74 (11), 2313-15 (CA 76,45892c, 1972), report the preparation of ω-(p-carboxyphenoxy)alkanoicacids and their dimethyl esters.

U.S. Pat. No. 3,637,595 discloses liquid crystal copolyesters preparedfrom terephthalic acid, hydroquinone, and p-hydroxybenzoic acid.

British Patent Nos. 1,507,207 and 1,508,646 (equivalent to German OS No.2,520,820) disclose liquid crystal polyesters prepared from a variety ofdihydric phenols and aromatic dicarboxylic acids.

In Shalaby et al., U.S. patent application Ser. No. 392,331, filed June29, 1982 and assigned to the same assignee as this application, there isdisclosed radiation sterilizable, absorbable polymers derived from1,4-phenylene-bis-oxyacetic acid, including copolymers derived frompoly(alkylene 1,4-phenylene-bis-oxyacetate) and glycolide and/orlactide.

In Bezwada et al., U.S. patent application Ser. No. 459,42, filed Jan.20, 1983, and assigned to the same assignee as this application, thereis disclosed radiation sterilizable, absorbable polymers derived from4-(carboxymethoxy)benzoic acid and glycolide and/or lactide.

U.S. Pat. No. 2,516,955 (Butler et al.) discloses esters ofphenylene-bis-oxyacetic acid and monohydric alcohols.

Low molecular weight polyesters of phenylene-bis-oxyacetic acid areclaimed to have been produced by Spanagel and Carouthers, as reported inJACS, 57, pages 935-936 (1935).

Doddi et al., in U.S. Pat. No. 4,052,988, discloses synthetic absorbablesutures and other surgical devices produced from polymers ofp-dioxanone.

DETAILED DESCRIPTION OF THE INVENTION

The polymers of the invention are copolyesters that are preferablyproduced by the reaction of (a) p-dioxanone monomer, and (b) a basepolyester of a dihydric alcohol and a phenylene-bis-oxyacetic acidand/or a carboxymethoxybenzoic acid.

The preferred procedures for the preparation of the base polyesters andthe diacids or diesters used to make them are illustrated by Examples1-9:

EXAMPLE 1 Preparation of Dimethyl Ester of 4-(carboxymethoxy)benzoicAcid ##STR1## 152.2 Grams (1 mole) of methyl p-hydroxybenzoate, 130.2grams (1.2 mole) of methyl chloroacetate, and 427 milliliters ofanhydrous methanol are charged into a 2-liter, 3-neck, round bottomflask fitted with an addition funnel with a nitrogen inlet, a mechanicalstirrer, a reflux condenser with a drying tube, a thermometer, and aheating mantle. The reaction mixture is refluxed for 30-60 minutes. Asolution of sodium methoxide in methanol (216.1 grams, 25% by weight, or1 mole of sodium methoxide) is added through the addition funnel in 1-2hours at reflux. After the addition is completed, the stirred reactionmixture is refluxed for about 16 hours under nitrogen. One milliliter ofglacial acetic acid is added to make sure that the reaction mixture isnot basic. The hot solution is then filtered to remove the precipitatedsodium chloride. Upon cooling the mother liquor, white crystallinematerial is precipitated. The crystals are filtered, dried, and are thenrecrystallized twice from anhydrous methanol using 3.5 milliliters pergram of dried product. The product has a melting point of 94°-95.5° C.with an overall yield of 163 grams of the dimethyl ester of4-(carboxymethoxy)benzoic acid (72.7%).

The corresponding 1,2- and 1,3- isomers are derived by analogousprocedures from methyl salicylate and methyl m-hydroxybenzoate,respectively. In those aspects of the invention wherein R in thedivalent unit (C) is alkyl, a substituted alpha-chloroacetic ester isused in place of methyl chloroacetate. Examples include methylalpha-chloropropionate, methyl alpha-chlorobutyrate, and methylalpha-chlorohexanoate.

The benzene ring in the hydroxybenzoic acid starting reactant cancontain substituent groups such as lower alkyl (e.g., methyl) or loweralkoxy (e.g., methoxy) that do not interfere with the esterificationreactions to which the monomer will be subjected in producing thecopolyester of the invention.

EXAMPLE 2 Preparation of Dimethyl 1,4-Phenylene-bis-oxyacetate

A dry 5-liter, 3-neck round bottom flask equipped with an additionfunnel with a nitrogen inlet, a mechanical stirrer, and a refluxcondenser with drying tube, a thermometer and a heating mantle ischarged with 330.3 grams (3 moles) of hydroquinone, 651.2 grams (6moles) of methyl chloroacetate, and 1722 ml. of methanol. The contentsof the flask are brought to reflux (approximately 68° C.) after aninitial purge with nitrogen. A solution of sodium methoxide in methanol(1183 grams, 27.4 weight percent or 6 moles of sodium methoxide), ischarged to the addition funnel and allowed to slowly enter the refluxingreaction solution over the course of approximately one hour.

After the addition is completed, the reaction mixture is allowed toreflux an additional 17 hours during which time the reflux temperaturedrops to 65° C. Glacial acetic acid (about 2 milliliters) is added tomake sure the solution is not basic. The solution is filtered while hot(above 60° C.) to remove the precipitated sodium chloride. The filtrateis cooled and a white crystalline material precipitates. The crystalsare filtered and a dry weight of 498.9 grams is obtained. The crystalsare twice recrystallized from methanol using 4 ml of methanol per gramof dry weight of crystals to result in dimethyl1,4-phenylene-bis-oxyacetate having a melting point of 97°-98° C., withan overall yield of at least 55.4%.

Just as was the case with the aspect of the invention illustrated byExample 1, a substituted alpha-chloracetic acid ester can be used toproduce polymers wherein R in (C) is alkyl.

EXAMPLE 3 Preparation of the dimethyl ester of1,3-phenylene-bis-oxyacetate ##STR2## A dry 3-liter, 3-neck, roundbottom flask equipped with an addition funnel, a nitrogen inlet, areflux condenser with a drying tube, and a mechanical stirrer, ischarged with 220.2 grams (2 moles) of resorcinol, 434.1 grams (4 moles)of methyl chloroacetate, and 798 milliliters of methanol. The contentsof the flask are heated to reflux for 30 minutes after an initial purgewith nitrogen. A solution of sodium methoxide in methanol (864.3 grams,25.0 weight percent or 4 moles of sodium methoxide) is charged to theaddition funnel, and added slowly to the refluxing reaction solutionover the course of approximately two hours.

After the addition is completed, the reaction mixture is allowed toreflux an additional 17 hours. Two milliliters of glacial acetic acid isadded to render the reaction mixture mildly acidic. The solution is hotfiltered to remove the sodium chloride. Upon cooling the filtrate, whitecrystalline material is precipitated. The crystals are filtered and adry weight of 296.0 grams is obtained. The crystals are recrystallizedusing 3 milliliters of methanol per gram of dry weight of crystals toresult in 134 grams of product. It was recrystallized again using 2milliliters of methanol per gram of dry crystals to result in dimethyl1,3-phenylene-bis-oxyacetate having a melting point of 60.5°-61.5° C.and with an overall yield of 24.4 percent.

Preparation of Base Polyester

The base polyesters can be produced by a transesterification or anesterification reaction between a dihydric alcohol of Formula II:

II. HO--G--OH

and a compound of Formula III:

III. R'--O --CO--(--CHR--O--)_(m) Ph--O--CHR--CO--O --R'

wherein G, Ph, and m have the meanings set forth above, and wherein R ishydrogen or lower alkyl such as methyl, ethyl, or propyl, and wherein R'is hydrogen, lower alkyl such as methyl, ethyl, or isopropyl, or phenyl.

The dihydric alcohols that can be employed to produce the basepolyesters, which can be used singly or in mixtures, include C₂ to C₈alkylene glycols such as ethylene glycol, 1,2- and 1,3-propylene glycol,1,4-butylene glycol, 1,6-hexylene glycol, and the like; polyalkyleneglycols such as diethylene glycol, triethylene glycol,poly(oxytetramethylene) glycol, and the like; cycloaliphatic diols suchas 1,4-cyclohexanedimethanol, and the like; and aromatic dihydricalcohols such as 1,4-bis(2-hydroxyethoxy)benzene, and the like. Thepolymethylene glycols having three to six carbon atoms are preferred.1,3-Propylene glycol is most preferred.

The compounds of Formula III are preferably lower alkyl diesters such asthe dimethyl diesters, because they are the most convenient to use in atransesterification reaction. The corresponding half esters or diacidscan also be used, if desired, but are usually not preferred.

The dihydric alcohol and the diester (or half ester or diacid) areusually reacted in proportions of from about 1.1 to about 4 moles ofdihydric alcohol per mole of diester (or half ester or diacid).

A catalytically effective amount of a transesterification catalyst, withor without an esterification catalyst, is used in the reaction. Whilethe reaction would proceed with a wide variety of such catalysts, as apractical matter because the polymers of the invention are intended foruse in absorbable products, biologically acceptable catalysts used invery small amounts are preferred. Specific examples of such catalystsare stannous octoate and dibutyltin oxide. Illustrative proportions arefrom about 750 to about 30,000, and preferably about 1500 to about15,000 moles of monomer (i.e., moles of the compound of Formula III) permole of catalyst.

EXAMPLE 4 Preparation of polyester of 1,3-propylene glycol and1,4-phenylene-bis-oxyacetic acid ##STR3## Under a dry nitrogenatmosphere, the following materials were charged into a flame and vacuumdried, two-liter, three-neck, round bottom flask, equipped with a vacuumtight stainless steel paddle stirrer, a short distillation head fittedwith a receiver, and an adapter with a hose connection:

444.5 grams Dimethyl 1,4-Phenylene-bis-oxyacetate (1.75 moles)

336.8 grams 1,3-Propanediol (4.42 moles)

0.0253 gram Stannous Octoate (6.25×10⁻⁵ mole)

(In this Example and in other Examples where it is used, the stannousoctoate is added as a solution in toluene.)

After stoppering the flask, the contents of the flask were purged withnitrogen and then subjected to reduced pressure for several hours. Thecharged reaction vessel was then vented with nitrogen, closed off, andplaced in an oil bath. Under nitrogen at one atmosphere pressure, thereaction mixture was melted using a bath temperature of 120° C.

Once the charge was liquified, the reaction flask was connected to anefficient mechanical stirrer and thorough mixing at 120° C. wasperformed for one-half hour. While still under an atmosphere ofnitrogen, the molten reactants were subjected to the following heatingsequence: 160° C. for 1.25 hours; 175° C. for 1.5 hours; 190° C. for 2.5hours; 205° C. for 2 hours; and 220° C. for 2.25 hours.

After the 2.25 hours at 220° C., the receiver containing the distillatewas replaced with an empty receiver. Gradually over the course of 0.75hour, the pressure in the reaction vessel was reduced to 0.05 millimeterof mercury. Under reduced pressure, the reaction mixture was heated at220° C. for a total of 22.5 hours. The reaction flask was removed fromthe oil bath, equilibrated with nitrogen, and then allowed to cool toroom temperature. The soft polymer was isolated by first chilling theflask in liquid nitrogen to freeze the polymer, breaking the flask, andcollecting the frozen polymer.

The polyester was amorphous and had an inherent viscosity of 0.84 dl/gm,measured at 25° C. at a concentration of 0.1 gm/dl inhexafluoroisopropyl alcohol ("HFIP").

EXAMPLE 5 Preparation of polyester of 1,3-propylene glycol and1,4-phenylene-bis-oxyacetic acid

Under a dry nitrogen atmosphere, the following materials were charged toa flame and vacuum dried, one-liter, three-neck, round bottom flask,equipped with a vacuum tight stainless steel paddle stirrer, a shortdistillation head fitted with a receiver, and an adapter with a hoseconnection:

254 grams Dimethyl 1,4-phenylene-bis-oxyacetate (1.0 mole)

190.2 grams 1,3-Propanediol (2.5 moles)

0.0144 gram Stannous Octoate (3.56×10⁻⁵ mole)

After stoppering the flask, the contents of the flask were purged withnitrogen and then subjected to reduced pressure for several hours. Thecharged reaction vessel was then vented with nitrogen, closed off, andthen placed in an oil bath. Under nitrogen at one atmosphere pressure,the reaction mixture was melted using a bath temperature of 120° C. Oncethe charge was liquified, the reaction flask was connected to anefficient mechanical stirrer and thorough mixing at 120° C. wasperformed for one-half hour. While still under an atmosphere ofnitrogen, the molten reaction mixture was subjected to the followingheating sequence: 160° C. for 1.0 hour; 175° C. for 1.0 hour; 190° C.for 2.0 hours; 205° C. for 2.5 hours; and 220° C. for 2.0 hours.

After the 2.0 hours at 220° C., the receiver containing the distillatewas replaced with an empty receiver. Gradually over the course of 0.75hour, the pressure in the reaction vessel was reduced to 0.05 millimeterof mercury. Under reduced pressure, the reaction mixture was heated at220° C. for a total of 11.25 hours. After this step, the reaction flaskwas removed from the oil bath, equilibrated with nitrogen, and thenallowed to cool to room temperature. The soft polymer was isolated afterchilling in liquid nitrogen as described above.

The polyester was amorphous and had an inherent viscosity of 0.81 dl/gmin HFIP.

EXAMPLE 6 Preparation of Polyester of 1,6-hexanediol and1,4-phenylene-bis-oxyacetic acid ##STR4## Under a dry nitrogenatmosphere, the following materials were charged to a flame and vacuumdried, 250-ml, round bottom flask, equipped with a vacuum tightstainless steel paddle stirrer, a short distillation head fitted with areceiver, and an adapter fitted with a hose connection:

50.8 grams Dimethyl 1,4-phenylene-bis-oxyacetate (0.20 mole)

24.8 grams 1,6-Hexanediol (0.21 mole)

0.0036 gram Dibutyltin Oxide (1.45×10⁻⁵ mole)

After stoppering the flask, the contents of the flask were purged withnitrogen and then subjected to reduced pressure for several hours. Thecharged reaction vessel was then vented with nitrogen, closed off, andplaced in an oil bath. While under nitrogen at one atmosphere, thestirred molten reactants were subjected to the following heatingsequence: 160° C. for 1.5 hours; 190° C. for 0.5 hour; and 220° C. for1.0 hour.

After the 1.0 hour at 220° C., the receiver containing the distillatewas replaced with an empty receiver. Gradually over the course of 0.75hour, the pressure in the reaction vessel was reduced to 0.05 millimeterof mercury. Under reduced pressure, the reaction mixture was heated at220° C. for 1.5 hours and at 230° C. for 3.5 hours. After this step, thereaction flask was removed from the oil bath, equilibrated withnitrogen, and then allowed to cool to room temperature. The soft polymerwas isolated after chilling in liquid nitrogen, as described above. Thepolyester had a melting point of 65-70° C. and an inherent viscosity of0.36 dl/gm in HFIP.

EXAMPLE 7 Preparation of Polyester of 1,6-hexanediol and1,4-phenylene-bis-oxyacetic acid ##STR5## Under a dry nitrogenatmosphere, the following materials were charged to a flame and vacuumdried, 250-ml, twoneck, round bottom flask, equipped with a vacuum tightstainless steel paddle stirrer, a short distillation head fitted with areceiver, and an adapter fitted with a hose connection:

50.8 grams Dimethyl 1,4-Phenylene-bis-oxyacetate (0.20 mole)

24.8 grams 1,6-hexanediol (0.21 mole)

0.0036 gram Dibutyltin Oxide (1.45×10⁻⁵ mole)

After stoppering the flask, the contents were purged with nitrogen andthen exposed to reduced pressure for several hours. The charged reactionvessel was vented with nitrogen, closed off, and placed in an oil bath.Under an atmosphere of nitrogen, the reaction mixture was melted using abath temperature of 120° C. Once the charge was liquified, the reactionflask was connected to an efficient mechanical stirrer and thoroughmixing at 120° C. was performed for one-half hour. While still undernitrogen, the molten reactants were subjected to the following heatingsequence: 160° C. for 1.5 hours; 190° C. for 0.5 hours; and 220° C. for1.0 hour.

After the 1.0 hour at 220° C., the receiver containing the distillatewas replaced with an empty receiver. Then gradually over the course of0.75 hour, the pressure in the reaction vessel was reduced to 0.05millimeter of mercury. Under reduced pressure, the reaction mixture washeated at 220° C. for 1.0 hour. After this step, the reaction flask wasremoved from the oil bath, equilibrated with nitrogen, and then allowedto cool to room temperature. The soft polymer was isolated afterchilling in liquid nitrogen as described above. The polyester had amelting point of 70°-75° C. and an inherent viscosity in HFIP of 0.63dl/gm.

EXAMPLE 8 Preparation of Polyester From 1,3-Propanediol and dimethyl1,3-phenylene-bis-oxyacetate ##STR6## A flame dried, mechanicallystirred, 250-milliliter glass reactor (suitable for polycondensationreaction) is charged with 63.6 grams (0.25 mole) of dimethyl1,3-phenylene-bis-oxyacetate, 57.1 grams (0.75 mole) of 1,3-propanediol,and 0.114 ml. of 0.33M stannous octoate in toluene (0.015 mole percentbased on the diester monomer). After purging the reactor and ventingwith nitrogen, the contents of the reaction flask are melted using anoil bath temperature of 165° C. The temperature of the oil bath israised to 210° C. in 30 minutes and is maintained at 210° C. for 2hours, and at 220° C. for 3 hours while still under a nitrogenatmosphere, during which time the methanol formed is collected. Thereactor is allowed to cool to room temperature overnight. The next day,the reaction flask is heated slowly under reduced pressure (0.015-1.0mm) to 210° C. within 6 to 8 hours, and is maintained for 4 hours at210° C., during which time the distillates are collected. The polymer isisolated, ground, and dried in a vacuum oven at room temperature. Theresulting polymer has an inherent viscosity of 0.60 dl/g inhexafluoroisopropyl alcohol at 25° C. and 0.1 g/dl concentration.EXAMPLE 9 Preparation of polyester of 1,3-propanediol and4-(carboxymethoxy)benzoic acid ##STR7## A flame dried, mechanicallystirred, 100-milliliter glass reactor (suitable for polycondensationreactions) is charged with 89.7 grams (0.4 mole) of the dimethyl esterof 4-(carboxymethoxy)benzoic acid, 76.10 grams (1.0 mole) of1,3-propanediol, and 7.16 milligrams of dibutyltin oxide. After purgingthe reactor and venting with nitrogen, the contents of the reactionflask are melted in an oil bath at 160° C. The temperature of the oilbath is raised to 190° C. in 2 hours and is maintained at 190° C. for 2hours and then at 210° C. for 2 hours, during which time the methanolformed is collected. The reactor is allowed to cool to room temperatureovernight. The next day, the reaction flask is heated slowly underreduced pressure (0.05-1.0 mm) to 210° C. within 3 hours and 30 minutes,and is maintained for 4 hours and 15 minutes at 210° C., during whichtime the distillates are collected. The polymer is isolated, ground, anddried in a vacuum oven at room temperature. The resulting polymer has aninherent viscosity of 0.58 dl/g in hexafluoroisopropyl alcohol at 25° C.and 0.1 g/dl concentration. The base polyesters are usually essentiallynoncrystalline materials, or display low levels of crystallinity, havingmolecular weights in excess of about 2000, and having inherentviscosities of at least about 0.2 dl/gm, tested at a concentration of0.1 gm/dl in hexafluoroisopropyl alcohol at 25° C. Preparation ofCopolyester

The copolyesters of the invention are produced by reacting the basepolyester with p-dioxanone.

The co-esterification reaction is preferably carried out by dissolvingthe polyester in p-dioxanone, and then subjecting the reaction mixtureto elevated temperature for a period of time sufficient to produce thecopolyester of the invention. An additional esterification catalystsystem may be added for this second polymerization, or the initialcatalyst that remains in the reaction mixture from the preparation ofthe base polyester may be sufficient to catalyze the reaction.

The proportion of polyester to p-dioxanone is selected so that theresulting copolyester will be absorbable and will be able to withstandradiation sterilization while still maintaining a useful level ofphysical and biological properties. Typically, the copolyester willcontain from about 59 to 99 weight percent, and preferably (for sutureapplications) from 75 to 90 weight percent, of polymerized p-dioxanone.Routine experimentation will suffice to determine the proportions ofbase polyester and p-dioxanone monomer that should be used in particularcases to achieve the desired proportion in the copolyester product. TheExamples herein illustrate typical percent conversions of monomer. It isnoted that solid state polymerization (e.g., Example 11) usually yieldsa higher percent converstion than melt polymerization (e.g., Example10).

The following Examples 10-19 illustrate the preparation of thecopolyesters:

EXAMPLE 10 Preparation of copolyester of p-dioxanone and polyester of1,3-propanediol and 1,4-phenylene-bis-oxyacetic acid

To a dry, 250-milliliter, single-neck, round bottom flask was added 9.0grams of poly(trimethylene 1,4-phenylene-bis-oxyacetate) having aninherent viscosity in hexafluoroisopropyl alcohol of 0.81 dl/gram(Example 5). The contents of the flask were dried by exposure to highvacuum (less than 0.05 millimeter of mercury) for several hours at roomtemperature, followed by heating at 110° C. for 16 hours under highvacuum. The following materials were then added to the dried contents ofthe flask, under a dry nitrogen atmosphere:

57.6 grams p-dioxanone (0.565 mole)

0.0076 gram Stannous Octoate (1.88×10⁻⁵ mole)

A flame dried vacuum tight stainless steel paddle stirrer and an adapterwith a hose connection were attached to the charged reaction flask, andthe pressure in the reaction assembly was reduced to a low level forseveral hours. The reaction flask was then vented with nitrogen, closedoff, and placed in an oil bath. Under an atmosphere of dry nitrogen, thereaction mixture was heated, with initially rapid mechanical stirring tofacilitate dissolution of the polyester in the monomer, according to thefollowing temperature/time sequence:

80° C./1.75 hrs.

100° C./7.25 hrs. (The stirring rate was slowed as the viscosity of thepolymerizing mass increased.)

The resulting copolyester was isolated after chilling in liquid nitrogenas described above, and then ground. After exposure to vacuum at roomtemperature for 16 hours, the ground copolyester was heated at 80° C.and a pressure of 0.05 millimeter of mercury for 26 hours to removeunreacted p-dioxanone from the desired copolyester product; a 35.9%weight loss was observed. (Removal of unreacted monomer can also beeffected by vented screw extrusion. This latter procedure is preferredwhen the content of unreacted monomer is relatively high, e.g., over 15weight percent.) The resulting copolyester product had an inherentviscosity of 1.87 dl/gm measured at 25° C. and a concentration of 0.1gram/dl in hexafluoroisopropyl alcohol.

EXAMPLE 11 Preparation of copolyester of p-dioxanone and polyester of1,3-propanediol and 1,4-phenylene-bis-oxyacetic acid

To a dry, 100-milliliter, single-neck, round bottom flask was added 4.14grams of poly(trimethylene 1,4-phenylene-bis-oxyacetate) having aninherent viscosity in hexafluoroisopropyl alcohol of 0.87 dl/gram. Thecontents of the flask were dried by exposure to high vacuum (less than0.05 millimeter of mercury) for several hours at room temperature,followed by heating at 90° C. for 15 hours under high vacuum. Thefollowing materials were next added to the dried contents of the flask,under a dry nitrogen atmosphere:

23.5 grams p-Dioxanone (0.23 mole)

0.00468 gram Stannous Octoate (1.16×10⁻⁵ mole)

A flame dried vacuum tight stainless steel paddle stirrer and an adapterwith a hose connection were attached to the charged reaction flask, andthe pressure in the reaction assembly was reduced to a low level forseveral hours. The reaction flask was vented with nitrogen, closed off,and placed in an oil bath. Under dry nitrogen at one atmosphere, thereaction mixture was heated, with initially rapid mechanical stirring,according to the following temperature/time sequence:

80° C./1.0 hr.

90° C./27.0 hrs.

80° C./88.0 hrs.

(Stirring was slowed and eventually stopped when the viscosity of thepolymerizing mass became so great as to virtually prevent furtherstirring.)

The resulting copolyester was isolated after chilling in liquid nitrogenas described above, and then ground. After exposure to vacuum at roomtemperature for 16 hours, the ground copolyester was heated at 80° C.and a pressure of 0.05 millimeter of mercury for 16 hours to removeunreacted p-dioxanone from the desired copolyester product; an 8.6%weight loss was observed. The resulting copolyester product had aninherent viscosity of 1.84 dl/gm measured at 25° C. at a concentrationof 0.1 gram/dl in hexafluoroisopropyl alcohol, and a melting point of105°-111° C. (by thermal microscopy).

EXAMPLE 12 Preparation of copolyester of p-dioxanone and polyester of1,3-propanediol and 1,4-phenylene-bis-oxyacetic acid

To a dry, 250-milliliter, single-neck, round bottom flask was added 9.0grams of poly(trimethylene 1,4-phenylene-bis-oxyacetate) having aninherent viscosity in hexafluorisopropyl alcohol of 0.63 dl/gram. Thecontents of the flask were dried by exposure to a high vacuum (less than0.05 millimeter of mercury) for several hours at room temperature,followed by heating at 90° C. for 12 hours under high vacuum. Thefollowing materials were then added to the dried contents of the flask,under a dry nitrogen atmosphere:

81.0 grams p-Dioxanone (0.794 mole)

0.0160 gram Stannous Octoate (3.96×10⁻⁵ mole)

A flame dried vacuum tight stainless steel paddle stirrer and an adapterwith a hose connection were attached to the charged reaction flask, andthe pressure in the reaction assembly was reduced to a low level forseveral hours. The reaction flask was then vented with nitrogen andplaced in an oil bath. Under a dry nitrogen atmosphere, the reactionmixture was heated, with initially rapid mechanical stirring, accordingto the following temperature/time sequence:

80° C./1.0 hr.

90° C./27.0 hrs.

80° C./88.0 hrs.

(Stirring was slowed and eventually stopped when the viscosity of thepolymerizing mass became so great as to virtually prevent furtherstirring.)

The resulting copolyester was isolated after chilling in liquidnitrogen, and was then ground. After exposure to vacuum at roomtemperature for 16 hours, the ground copolyester was heated at 80° C.and a pressure of 0.05 millimeter of mercury for 16 hours to removeunreacted p-dioxanone from the desired copolyester product; an 11.2%weight loss was observed. The resulting copolyester product had aninherent viscosity of 1.74 dl/gm measured at 25° C. at a concentrationof 0.1 gram/dl in hexafluoroisopropyl alcohol, and a melting point (bythermal microscopy) of 107°-111° C.

EXAMPLE 13 Preparation of copolyester of p-dioxanone and polyester of1,3-propanediol and 1,4-phenylene-bis-oxyacetic acid

To a dry, 2-liter, three-neck, round bottom flask was added 75.0 gramsof poly(trimethylene 1,4-phenylene-bis-oxyacetate) having an inherentviscosity in hexafluoroisopropyl alcohol of 0.81 dl/gram (Example 5).The contents of the flask were dried by exposure to high vacuum (lessthan 0.05 millimeter of mercury) for several hours at room temperature,followed by heating at 110° C. for 16 hours under high vacuum. Thefollowing materials were added to the dried contents of the flask, undera dry nitrogen atmosphere:

425.0 grams p-Dioxanone (4.17 moles)

0.0842 gram Stannous Octoate (2.08×10⁻⁴ mole)

A flame dried vacuum tight stainess steel paddle stirrer and an adapterwith a hose connection were attached to the charged reaction flask, andthe pressure in the reactor was reduced to a low level for severalhours. The reaction flask was vented with nitrogen, closed off, andplaced in an oil bath. Under a dry nitrogen atmosphere, the reactionmixture was heated, with initially rapid mechanical stirring, accordingto the following temperature/time sequence:

75° C./2.25 hrs.

90° C./3.0 hrs.

80° C./135 hrs.

(Stirring was slowed and eventually stopped when the viscosity of thepolymerizing mass became so great as to virtually prevent furtherstirring.)

The resulting copolyester was isolated after chilling in liquidnitrogen, and then ground. After exposure to vacuum at room temperaturefor 16 hours, the ground copolyester was heated at 80° C. and a pressureof 0.05 millimeter of mercury for 62 hours to remove unreactedp-dioxanone from the desired copolyester product; an 11.8% weight losswas observed. The resulting copolyester product had an inherentviscosity of 2.18 dl/gm measured at 25° C. and a concentration of 0.1gram/dl and 25° C. in hexafluoroisopropyl alcohol, and a melting point(by thermal microscopy) of 109°-111° C.

EXAMPLE 14 Preparation of copolyester of p-dioxanone and polyester of1,6-hexanediol and 1,4-phenylene-bis-oxyacetic acid

To a dry, 500-milliliter, single-neck, round bottom flask was added 4.5grams of poly(hexamethylene 1,4-phenylene-bis-oxyacetate) having aninherent viscosity in hexafluoroisopropyl alcohol of 0.63 dl/gram(Example 7). The contents of the flask were dried by exposure to highvacuum (less than 0.05 millimeter of mercury) for several hours at roomtemperature, followed by heating at 90° C. for 15 hours under highvacuum. The following materials were added to the dried contents of theflask, under a dry nitrogen atmosphere:

85.5 grams p-Dioxanone (0.838 mole)

0.0170 gram Stannous Octoate (4.19×10⁻⁵ mole)

A flame dried vacuum tight stainless steel paddle stirrer and an adapterwith a hose connection were attached to the charged reaction flask, andthe pressure in the reactor was reduced to a low level for severalhours. The reaction flask was vented with nitrogen, closed off, andplaced in an oil bath. Under a dry nitrogen atmosphere, the reactionmixture was heated, with initially rapid mechanical stirring, accordingto the following temperature/time sequence:

80° C./1.0 hr.

90° C./27.0 hrs.

80° C./88.0 hrs.

(Stirring was slowed and eventually stopped when the viscosity of thepolymerizing mass became so great as to virtually prevent furtherstirring.)

The resulting copolyester was isolated after chilling in liquidnitrogen, and then ground. After exposure to vacuum at room temperaturefor 16 hours, the ground copolyester product was heated at 80° C. and apressure of 0.05 millimeter of mercury for 16 hours to remove unreactedp-dioxanone from the desired copolyester product; a 3.9% weight loss wasobserved. The resulting copolyester product had an inherent viscosity of2.29 dl/gm measured at 25° C. at a concentration of 0.1 gram/dl inhexafluoroisopropyl alcohol, and a melting point of 104°-114° C. (bythermal microscopy).

EXAMPLE 15 Preparation of copolyester of p-dioxanone and polyester of1,6-hexanediol and 1,4-phenylene-bis-oxyacetic acid

To a dry, 100-milliliter, single-neck, round bottom flask was added 3.0grams of poly(hexamethylene 1,4-phenylene-bis-oxyacetate) having aninherent viscosity in hexafluoroisopropyl alcohol of 0.36 dl/gram(Example 6). The contents of the flask were dried by exposure to highvacuum (less than 0.05 millimeter of mercury) for several hours at roomtemperature, followed by heating at 90° C. for 15 hours under highvacuum. The following materials were added to the dried contents of theflask, under a dry nitrogen atmosphere:

27.0 grams p-Dioxanone (0.265 mole)

0.00534 gram Stannous Octoate (1.32×10⁻⁵ mole)

A flame dried vacuum tight stainless steel paddle stirrer and an adapterwith a hose connection were attached to the charged reaction flask, andthe pressure in the reactor was reduced to a low level for severalhours. The reaction flask was vented with nitrogen, closed off, andplaced in an oil bath. Under a dry nitrogen atmosphere, the reactionmixture was heated, with initially rapid mechanical stirring, accordingto the following temperature/time sequence:

80° C./0.75 hr.

90° C./3.3 hrs.

80° C./112 hrs.

(Stirring was slowed and eventually stopped when the viscosity of thepolymerizing mass became so great as to virtually prevent furtherstirring.)

The resulting copolyester was isolated after chilling in liquidnitrogen, and then ground. After exposure to vacuum at room temperaturefor 16 hours, the ground copolyester product was heated at 80° C. and apressure of 0.05 millimeter of mercury for 16 hours to remove unreactedp-dioxanone from the desired copolyester product; a 11.2% weight losswas observed. The copolyester product had an inherent viscosity of 1.82dl/gm measured at 25° C. at a concentration of 0.1 gram/dl inhexafluoroisopropyl alchol, and a melting point (by thermal microscopy)of 109°-112° C.

EXAMPLE 16 Preparation of coplyester of p-dioxanone and polyester of1,3-propanediol and 1,3-phenylene-bis-oxyacetic acid

A flame dried, 100-milliliter, round bottom, one-neck flask is chargedunder nitrogen with 5 grams of the polyester of Example 8 and thecontents of the flask are held for about 16 hours at 115° C./0.1 mm. Tothe same flask, after drying, 45 grams of p-dioxanone and 0.58 ml of0.033M stannous octoate in toluene (0.00434 mole per cent, based onp-dioxanone monomer) are charged and then the flask is fitted with avacuum tight mechanical stirrer. The flask is dried under vacuum andpurged with nitrogen three times before being vented with nitrogen andimmersed in a silicone oil bath. The mixture is heated to and maintainedat about 85° C. with rapid stirring for one hour to melt the p-dioxanoneand to dissolve the polyester. The temperature of the oil bath is raisedto 90° C. and maintained for 24 hours at 90° C. The mechanical stirringis discontinued after 3 to 4 hours at 90° C. because of the viscousnature of the reaction mass. The temperature of the oil bath is loweredto 80° C. and is maintained there for 72 hours. The polymer is isolated,ground, and dried 18 hours/80° C./0.1 mm to remove any unreactedmonomer. A weight loss of 10.1% is observed. The resulting polymer has amelting range of about 104°-107° C. and an inherent viscosity of about2.2 dl/g at 25° C. and a concentration of 0.1 g/dl inhexafluoroisopropyl alcohol.

EXAMPLE 17 Preparation of copolyester of p-dioxanone and polyester of1,3-propanediol and 4-(carboxymethoxy)benzoic acid

A flame dried, 250 milliliter, round bottom, one-neck flask is chargedunder nitrogen with 10 grams of the polyester of Example 9 and the flaskis held for about 16 hours at 50° C./0.1 mm. To the same flask, afterdrying, 90 grams of p-dioxanone and 0.133 ml of 0.33M stannous octoatein toluene (0.005 mole percent, based on p-dioxanone monomer) arecharged and then the flask is fitted with a mechanical stirrer. Theflask is dried under vacuum and purged with nitrogen three times beforebeing vented with nitrogen and immersed in a silicone oil bath. Themixture is heated to and maintained at about 85° C. with rapid stirringfor one hour to melt the p-dioxanone and to dissolve the polyester. Thetemperature of the oil bath is raised to 90° C. and maintained for 24hours at 90° C. The mechanical stirring is discontinued after 3 to 4hours at 90° C. because of the viscous nature of the reaction mass. Thetemperature of the oil bath is lowered to 80° C. and is maintained therefor 72 hours. The polymer is isolated, ground, and dried for 36hours/80° C./0.1 mm to remove any unreacted monomer. A total of 12.72%monomer is removed due to drying. The resulting polymer has a meltingrange of about 106°-110° C. and an inherent viscosity of about 1.88 dl/gat 25° C. and a concentration of 0.1 g/dl in hexafluoroisopropylalcohol.

EXAMPLE 18 Preparation of copoyester of p-dioxanone and polyester of1,3-propanediol and 1,3-phenylene-bis-oxyacetic acid

A flame dried, 250-milliliter, round bottom, one-neck flask is chargedunder nitrogen with 15 grams of the polyester of Example 8 and thecontents of the flask are held for about 16 hours at 115° C./0.1 mm. Tothe same flask, after drying, 85 grams of p-dioxanone and 0.10milliliter of 0.33M stannous octoate in toluene (0.00396 mole percentbased on p-dioxanone monomer) are charged and the flask is fitted with aflame dried mechanical stirrer and an adapter with a hose connection.The reactor is purged with nitrogen three times before being vented withnitrogen. The reactor is connected to a gas supply to maintain nitrogenat a pressure of one atmosphere for the remainder of the run and then isimmersed in a silicone oil bath. The mixture is heated to and maintainedat about 80° C. for one hour to melt the p-dioxanone and to dissolve thepolyester. The temperature of the oil bath is raised to 90° C. and ismaintained there for 24 hours. The mechanical stirring is discontinuedafter 3 to 4 hours at 90° C. because of the viscous nature of thereaction mass. The temperature of the oil bath is lowered to 80° C. andmaintained there for 72 hours. The polymer is isolated, ground, anddried 18 hours/80° C./0.1 mm to remove any unreacted monomer. A weightloss of 12.8% is observed. The resulting polymer has a melting range ofabout 105°-108° C. and an inherent viscosity of about 1.82 dl/g at 25°C. and a concentration of 0.1 g/dl in hexafluoroisopropyl alchol.

EXAMPLE 19 Preparation of copolyester of p-dioxanone and polyester of1,3-propanediol and 4-(carboxymethoxy)benzoic acid

A flame dried, 250-milliliter, round bottom, one-neck flask is chargedunder nitrogen with 15 grams of the polyester of Example 9 and the flaskis held for about 16 hours at 50° C./0.1 mm. To the same flask, afterdrying, 85 grams of p-dioxanone and 0.126 milliliter of 0.33M stannousoctoate in toluene (0.005 mole percent, based on p-dioxanone monomer)are charged and the flask is fitted with a mechanical stirrer and anadapter with a hose connection. The reactor is purged with nitrogenthree times before being vented with nitrogen. The reactor is connectedto a gas supply to maintain nitrogen at a pressure of one atmosphere forthe remainder of the run and then is immersed in a silicone oil bath.The mixture is heated to and maintained at about 75° C. for one hour tomelt the p-dioxanone and to dissolve the polyester. The temperature ofthe oil bath is raised to 90° C. and is maintained there for 24 hours.The mechanical stirring is discontinued after 3 to 4 hours at 90° C.because of the viscous nature of the reaction mass. The temperature ofthe oil bath is lowered to 80° C. and is maintained there for 72 hours.The polymer is isolated, ground, and dried for 18 hours/80° C./0.1 mm toremove any unreacted monomer. A total of 5.79% monomer is removed. Theresulting polymer has a melting range of about 107°-109° C. and aninherent viscosity of about 1.56 dl/g at 25° C. and a concentration of0.1 g/dl in hexafluoroisopropyl alchol.

Control 1

Under a dry nitrogen atmosphere, p-dioxanone (155.2 grams, 1.52 moles),1-dodecanol (0.473 gram, 2.54 millimoles, 4.73 milliters of a 0.537Mtoluene solution), and a catalytic amount of stannous octoate (0.115milliliter of a 0.33M toluene solution, 0.038 millimoles) were added toa flame and vacuum dried 500 milliliter glass ampoule, equipped with amagnetic stirring bar. The contents of the ampoule were exposed tovacuum at room temperature for several hours with intermittant drynitrogen purges. The glass ampoule was sealed under partial vacuum,placed in a silicone oil bath, and its contents heated (with rapidmagnetic mixing as melting viscosity allowed) according to the followingtemperature/time scheme:

120° C./1 Minute

90° C./3 Hours

80° C./96 Hours

The resulting polyester was isolated by immersing the glass ampoule inliquid nitrogen and shattering the surrounding glass with a heavyobject. The glass-free polymer was ground in a Wiley mill and storedunder vacuum for 16 hours at room temperature. The ground polymer washeated at 80° C. under a pressure of 0.05 millimeters of mercury for 16hours to remove any unreacted p-dioxanone. The polyester possessed aninherent viscosity of 1.79 dl/gm measured at 25° C. and a concentrationof 0.1 gram/dl in hexafluoroisopropyl alcohol.

The control polyester was spun at 155° C. at a shear rate of 213 sec⁻¹using an INSTRON Capillary Rheometer with a 40 mil die (L/D=24.1) and aram speed of 2 cm/min. An apparent melt viscosity of 6715 poise wasobserved. The fiber was taken up at 24 feet/minute after an ice waterquench; the wound fiber was dried and subsequently drawn one week later.

The control extrudate (diameter range: 17.0 to 18.5 mils) was drawn intwo stages employing a glycerine draw bath under the conditions of 4× at55° C. followed by 1.5× at 75° C. and subsequently water-washed anddried in vacuo at room temperature.

The control drawn monofilaments were annealed at 77° C. for 6 hours with5% relaxation.

The control annealed monofilaments were cut to appropriate lengths,placed in individual paper folders and heat-sealable vented foilenvelopes. The packages were subjected to 50° C. and 0.1 mm Hg pressurefor 72 hours to dry and subsequently sealed under nitrogen. Portions ofthe control packaged fibers were sterilized by exposure to 2.5 Mrads ofgamma radiation from a Co⁶⁰ source.

EXTRUSION

The copolyesters are melt extruded through a spinnerette in aconventional manner to form one or more filaments.

Extrusion of the copolyesters described herein was accomplished using anINSTRON Capillary Rheometer. The copolymers were packed in the preheated(80° to 90° C.) extrusion chamber and extruded through a 40 mil die(L/D=24.1) after a dwell time of 11 to 13 minutes at the extrusiontemperature and a ram speed of 2 cm/min. While extrusion temperaturesdepend both on the polymer Tm and on the melt viscosity of the materialat a given temperature, extrusion of the subject copolyesters attemperatures of about 10° to 75° C. above the Tm is usuallysatisfactory. The extrusion temperatures of the example copolyestersdescribed herein ranged from 155° to 185° C. The extrudate was taken upthrough an ice water quench bath at either 24, 28 or 38.5 feet/minute. Ascrew-type extruder or similar device can be substituted for the INSTRONCapillary Rheometer.

The extrudate filaments are subsequently drawn about 4× to 7× in a oneor multistage drawing process in order to achieve molecular orientationand improve tensile properties. The extrudates described herein weredrawn 2 hours to about 1 week after extrusion. (The length of timeelapsed between extrusion and drawing may effect the drawing process;the optimum time elapsed is easily determined by simple experimentationfor each fiber composition.) The manner of drawing is as follows:

The extrudate (diameter range, 13-20 mils) passed through rollers at aninput speed of four feet per minute and into a heated draw bath ofglycerine. The temperatures of the draw bath can vary from about 25° to90° C.; the examples described herein employ temperatures between 52°and 61° C. The draw ratio in this first stage of drawing can vary from3× to about 7×; the examples described herein employ draw ratios from 4×to 5×. The partially drawn fibers are then placed over a second set ofrollers into a glycerine bath (second stage) kept at temperaturesranging from 50° to 95° C.; the examples described herein employ secondstage draw temperatures of 69° to 84° C. Draw ratios of up to 2× areapplied in this second stage, but a ratio range of from 1.2× to 1.5× hasbeen employed in the examples. The fiber is passed through a water-wash,taken up on a spool, and dried. A set of hot rollers can be substitutedfor a portion or all of the glycerine draw bath. The resulting orientedfilaments have good straight and dry tensile strengths.

Dimensional stability and tensile strength retention of the orientedfilaments may be enhanced by subjecting the filaments to an annealingtreatment. This optional treatment consists of heating the drawnfilaments to a temperature of from about 40° to 90° C., most preferablyfrom about 60° to 80° C. while restraining the filaments to prevent anysubstantial shrinkage. This process may begin with the filamentsinitially under tension or with up to 20% shrinkage allowed prior torestraint. The filaments are held at the annealing temperature for a fewseconds to several days or longer depending on the temperature andprocessing conditions. In general, annealing at 60° to 80° C. for up toabout 24 hours is satisfactory for the copolyesters of the invention.Optimum annealing time and temperature for maximum fiber in vivostrength retention and dimensional stability is readily determined bysimple experimentation for each fiber composition.

The characteristic properties of the filaments of the invention arereadily determined by conventional test procedures. The tensileproperties (i.e., straight and knot tensile strengths, Young's Modulus,and elongation) displayed herein were determined with an INSTRON tensiletester. The settings used to determine the straight tensile, knottensile, break elongation, and Young's Modulus were the following,unless indicated:

    ______________________________________                                                   Gauge   Chart    Crosshead                                                    Length  Speed    Speed                                                        (cm)    (cm/min) (cm/min)                                          ______________________________________                                        Straight Tensile                                                                           12        20       10                                            Knot Tensile  5        10       10                                            Break Elongation                                                                           12        20       10                                            Young's Modulus                                                                            12        20       10                                            ______________________________________                                    

The straight tensile strength is calculated by dividing the force tobreak by the initial cross-sectional area of the fiber. The elongationto break is read directly from the stress-strain curve of the sampleallotting 4-1/6% per centimeter of horizontal displacement.

Young's Modulus is calculated from the slope of the stress-strain curveof the sample in the linear elastic region as follows: ##EQU1## θ is theangle between the slope and the horizontal, XS is the initialcross-sectional area of the fiber, SL is the scale load, XH is thecrosshead speed, CS is the chart speed, and GL is the gage length. TheSL may be selected to provide a θ close to 45°.

The knot tensile strength of a fiber is determined in separateexperiments. The test article is tied into a surgeon's knot with oneturn of the filament around flexible tubing of 1/4 inch inside diameterand 1/16 inch wall thickness. The surgeon's knot is a square knot inwhich the free end is first passed twice, instead of once, through theloop, and the ends drawn taut so that a single knot is superimposed upona compound knot. The first knot is started with the left end over theright end and sufficient tension is exerted to tie the knot securely.

The specimen is placed in the INSTRON tensile tester with the knotapproximately midway between the clamps. The knot tensile strength iscalculated by dividing the force required to break by the initialcross-sectional area of the fiber.

Conversion from metric dimensions to English dimensions (i.e. psi) ismade by applying the appropriate factors.

EXAMPLE 20

The copolyester of Example 15 is made into monofilament suture materialin accordance with the following extrusion, drawing, and annealingconditions:

EXTRUSION

The copolyester was spun at 185° C. at a shear rate of 213 sec⁻¹ usingan INSTRON Capillary Rheometer with a 40 mil die (L/D=24.1) and a ramspeed of 2 cm/min. An apparent melt viscosity of 3000 poise wasobserved. The fiber was taken up at 24 ft./min after an ice waterquench; the wound fiber was dried and subsequently drawn one week later.

DRAWING

The extrudate (diameter range: 17.0 to 18.5 mils) was drawn in twostages employing a glycerine draw bath under the conditions of 4× at 55°C. followed by 1.5× at 73° C. and subsequently water-washed and dried invacuo at room temperature.

ANNEALING

The drawn monofilament was annealed at 77° C. for 6 hours with 5%relaxation.

The annealed monofilaments were cut to appropriate lengths, placed inindividual paper folders and heat-sealable vented foil envelopes. Thepackages were subjected to 50° C. and 0.1 mm Hg pressure for 72 hours todry and subsequently sealed under nitrogen. Portions of the packagedfibers were sterilized by exposure to 2.5 M rads of gamma radiation froma Co⁶⁰ source. Table I, below, displays representative properties of thedried monofilament, both before and after sterilization, and comparesthe properties with a typical dried annealed drawn monofilament madefrom poly(p-dioxanone) homopolymer (Control 1):

                  TABLE I                                                         ______________________________________                                                         Straight        Young's                                              Diam.,   Tensile ×                                                                         Elong.,                                                                             Mod. ×                                                                          Fiber.sup.(1)                        Sample  Mils     10.sup.-3, psi                                                                          %     10.sup.-3, psi                                                                        I.V.                                 ______________________________________                                        Before Co.sup.60 Irradiation                                                  Example 20                                                                            8.0      56.7      43    218     1.52                                 Control 1                                                                             7.8      70.9      39    310     1.60                                 After Co.sup.60 Irradiation                                                   Example 20                                                                            8.1      50.4      42    225     1.13                                 Control 1                                                                             8.2      58.0      37    301     1.21                                 ______________________________________                                         .sup.(1) Inherent viscosity of the fiber, tested in HFIP at 25° C.     and a concentration of 0.1 gm/dl.                                        

BREAKING STRENGTH RETENTION

The breaking strength retention (BSR) of a fiber is determined byimplanting two strands of the fiber in the dorsal subcutis of each of anumber of Long-Evans rats. The number of rats used is a function of thenumber of implantation periods, employing 4 rats per period giving atotal of eight (8) examples for each of the periods. Thus 16, 24, or 32segments of each fiber are implanted corresponding to two, three, orfour implantation periods. The periods of in vivo residence are 7, 14,21, or 28 days. The ratio of the mean value of 8 determinations of thebreaking strength (determined with an INSTRON Tensile tester employingthe following settings: a gage length of 1 inch, a chart speed of 1inch/minute, and a crosshead speed of 1 inch/minute) at each period tothe mean value (of 8 determinations) obtained for the fiber prior toimplantation constitutes its breaking strength retention for thatperiod.

The results of the BSR tests for the packaged and Co⁶⁰ sterilizedmonofilament of Example 20 are displayed in Table II, compared with theBSR for Control 1 (also packaged and Co⁶⁰ sterilized):

                  TABLE II                                                        ______________________________________                                        In Vivo Breaking Strength Retention                                           Diam.,        Initial    % BSR                                                Sample  Mils      Strength, lbs.                                                                           14    21  28 (days)                              ______________________________________                                        Example 20                                                                            8.1       2.61       62    55  40                                     Control 1                                                                             8.2       3.08       43    30  25                                     ______________________________________                                    

EXAMPLE 21

The copolyester of Example 14 is made into monofilament suture materialin accordance with the following extrusion, drawing, and annealingconditions:

EXTRUSION

The copolyester was spun at 165° C. at a shear rate of 213 sec⁻¹ usingan INSTRON Capillary Rheometer with a 40 mil die (L/D=24.1) and a ramspeed of 2 cm/min. An apparent melt viscosity of 8100 poise wasobserved. The fiber was taken up at 24 ft/min after an ice water quench;the wound fiber was dried and subsequently drawn six days later.

DRAWING

The extrudate (diameter range: 19.0 to 20.0 mils) was drawn in twostages employing a glycerine draw bath under the conditions of 4× at 58°C. followed by 1.5× and 70° C. and subsequently water-washed and driedin vacuo at room temperature.

ANNEALING

The drawn monofilament was annealed at 80° C. for 6 hours with 5%relaxation.

The annealed monofilament was cut to appropriate lengths, placed inindividual paper folders and heat-sealable vented foil envelopes. Thepackages were subjected to 50° C. and 0.1 mm Hg pressure for 24 hours todry and subsequently sealed under nitrogen. Portions of the packagedfibers were sterilized by exposure to 2.5 M rads of gamma radiation froma Co⁶⁰ source. Table III, below, displays certain physical properties ofthe annealed monofilament of Example 21 prior to drying andsterilization as well as the in vivo breaking strength retention of thesterilized suture material.

                  TABLE III                                                       ______________________________________                                                 Diam.,  Tensile,   Elong.,                                                                             Young's mod.,                                        mils    psi        %     psi                                         ______________________________________                                        Non-Sterile                                                                            8.2     73,600     30    285,000                                     ______________________________________                                                  Initial Straight                                                              Breaking Strength,                                                                          % BSR                                                             lbs.            21    28 (days)                                   ______________________________________                                        Co.sup.60 sterilized                                                                      3.95            49    28                                          ______________________________________                                    

EXAMPLE 22

The copolyester of Example 11 is made into monofilament suture materialin accordance with the following extrusion, drawing, and annealingconditions:

EXTRUSION

The copolyester was spun at 175° C. at a shear rate of 213 sec⁻¹ usingan INSTRON Capillary Rheometer with a 40 mil die (L/D=24.1) and a ramspeed of 2 cm/min. An apparent melt viscosity of 3800 poise wasobserved. The fiber was taken up at 38.5 feet/minute after an ice waterquench; the wound fiber was dried and subsequently drawn 5 days later.

DRAWING

The extrudate (diameter range: 13.0 to 15.5 mils) was drawn in twostages employing a glycerine draw bath under the conditions of 4× at 53°C. followed by 1.25× at 72° C. and subsequently water-washed and driedin vacuo at room temperature.

ANNEALING

The drawn monofilament was annealed at 80° C. for 6 hours with 5%relaxation.

EXAMPLE 23

The copolyester of Example 12 is made into monofilament suture materialin accordance with the following extrusion, drawing, and annealingconditions:

EXTRUSION

The copolyester was spun at 155° C. at a shear rate of 213 sec⁻¹ usingan INSTRON Capillary Rheometer with a 40 mil die (L/D=24.1) and a ramspeed of 2 cm/min. An apparent melt viscosity of 5900 poise wasobserved. The fiber was taken up at 24 feet/minute after an ice waterquench; the wound fiber was dried and subsequently drawn the next day.

DRAWING

The extrudate (diameter range: 18.5 to 19.5 mils) was drawn in twostages employing a glycerine draw bath under the conditions of 4× at 56°C. followed by 1.5× at 72° C. and subsequently water-washed and dried invacuo at room temperature.

ANNEALING

The drawn monofilament was annealed at 80° C. for 6 hours with 5%relaxation.

EXAMPLE 24

The copolyester of Example 10 is made into monofilament suture materialin accordance with the following extrusion, drawing, and annealingconditions:

EXTRUSION

The copolyester was spun at 170° C. at a shear rate of 213 sec⁻¹ usingan INSTRON Capillary Rheometer with a 40 mil die (L/D=24.1) and a ramspeed of 2 cm/min. An apparent melt viscosity of 8800 poise wasobserved. The fiber was taken up at 28 feet/minute after an ice waterquench; the wound fiber was dried and subsequently drawn the next day.

DRAWING

The extrudate (diameter range 16.0 to 18.0 mils) was drawn in two stagesemploying a glycerine draw bath under the conditions of 5× at 61° C.followed by 1.2× at 69° C. and subsequently water-washed and dried invacuo at room temperature.

ANNEALING

The drawn monofilament was annealed at 80° C. for 61/4 hours with 5%relaxation.

The annealed monofilaments of Examples 22, 23, and 24 were cut toappropriate lengths, placed in individual paper folders andheat-sealable vented foil envelopes. The packages were subjected to 50°C. and 0.1 mm Hg pressure for 72 hours to dry and subsequently sealedunder nitrogen. Portions of the packaged fibers were sterilized byexposure to 2.5 Mrads of gamma radiation from a Co⁶⁰ source.Representative properties of the dried annealed monofilaments, bothbefore and after Co⁶⁰ sterilization are displayed below in Table IV.Control 1 (also packaged and Co⁶⁰ sterilized) is included for comparisonpurposes.

                  TABLE IV                                                        ______________________________________                                                    Straight          Young's                                         Diam.,      Tensile ×                                                                         Elong., Mod. ×                                                                           Fiber                                  Mils        10.sup.-3, psi                                                                          %       10.sup.-3, psi                                                                         I.V.                                   ______________________________________                                        Before Co.sup.60 Irradiation                                                  Ex. 22 6.2      60.9      42    163      1.62                                 Ex. 23 7.8      57.0      61    175      1.53                                 Ex. 24 7.4      56.8      47    111      1.67                                 Control 1                                                                            7.8      70.9      39    310      1.60                                 After Co.sup.60 Irradiation                                                   Ex. 22 7.0      49.9      45    153      1.48                                 Ex. 23 8.0      51.9      67    174      1.38                                 Ex. 24 7.8      48.5      55    115      1.69                                 Control 1                                                                            8.2      58        37    301      1.21                                 ______________________________________                                    

The in vivo breaking strength retention profiles of the sterilizedmonofilaments of Examples 22, 23, and 24 were determined. The resultsare displayed in Table V:

                  TABLE V                                                         ______________________________________                                                In vivo BSR                                                                   Initial                                                                       Strength,   BSR %                                                     Sample    lbs           21 days 28 days                                       ______________________________________                                        Ex. 22    1.69          61      47                                            Ex. 23    2.53          66      43                                            Ex. 24    2.34          71      57                                            Control 1 3.08          30      25                                            ______________________________________                                    

EXAMPLE 25

The copolyester of Example 16 is made into monofilament suture materialin accordance with the following extrusion, drawing, and annealingconditions:

EXTRUSION

The copolyester was spun at 165° C. at a shear rate of 213 sec⁻¹ usingan INSTRON Capillary Rheometer with a 40 mil die (L/D=24.1) and a ramspeed of 2 cm/min. An apparent melt viscosity of 9100 poise wasobserved. The fiber was taken up at 24 feet/minute after an ice waterquench; the wound fiber was dried and subsequently drawn the same day.

DRAWING

The extrudate (diameter range 16.0 to 19.5 mils) was drawn in two stagesemploying a glycerine draw bath under the conditions of 4× at 60° C.followed by 1.25× at 80° C. and subsequently water-washed and dried invacuo at room temperature.

ANNEALING

The drawn monofilament was annealed at 80° C. for 6 hours with 5%relaxation.

EXAMPLE 26

The copolyester of Example 17 is made into monofilament suture materialin accordance with the following extrusion, drawing, and annealingconditions:

EXTRUSION

The copolyester was spun at 170° C. at a shear rate of 213 sec⁻¹ usingan INSTRON Capillary Rheometer with a 40 mil die (L/D=24.1) and a ramspeed of 2 cm/min. An apparent melt viscosity of 2800 poise wasobserved. The fiber was taken up at 24 feet/minute after an ice waterquench; the wound fiber was dried and subsequently drawn the next day.

DRAWING

The extrudate (diameter range: 17.5 to 19.5 mils) was drawn in twostages employing a glycerine draw bath under the conditions of 4× at 52°C. followed by 1.5× at 70° C. and subsequently water-washed and dried invacuo at room temperature.

ANNEALING

The drawn monofilament was annealed at 80° C. for 6 hours with 5%relaxation.

The annealed monofilaments of Examples 25 and 26 were cut to appropriatelengths, placed in individual paper folders and heat-sealable ventedfoil envelopes. The packages were subjected to 50° C. and 0.1 mm Hgpressure for 72 hours to dry and subsequently sealed under nitrogen.Portions of the packaged fibers were sterilized by exposure to 2.5 Mrads of gamma radiation from a Co⁶⁰ source. Properties of the packagedmonofilaments, both sterile and non-sterile, are displayed below inTable VI:

                  TABLE VI                                                        ______________________________________                                                       Straight  Knot    Young's                                            Diam.,   Tensile, ×                                                                        Tensile ×                                                                       Mod., ×                                                                         Elong.,                              Sample                                                                              Mils     10.sup.-3, psi                                                                          10.sup.-3, psi                                                                        10.sup.-3, psi                                                                        %                                    ______________________________________                                        Before Co.sup.60 Irradiation                                                  Ex. 25                                                                              8.8      61.6      43.2    186     56                                   Ex. 26                                                                              7.7      59.4      46.0    279     47                                   After Co.sup.60 Irradiation                                                   Ex. 25                                                                              8.1      62.5      53.5    160     57                                   Ex. 26                                                                              7.7      54.6      45.7    272     51                                   ______________________________________                                    

The in vivo breaking strength retention profiles of the packagedmonofilaments of Example 25 before and after Co⁶⁰ sterilization weredetermined. The results are displayed in Table VII:

                  TABLE VII                                                       ______________________________________                                                In vivo BSR                                                                   Initial                                                                       Strength,                                                                              BSR %                                                        Sample    lbs.       7     14    21  28 (days)                                ______________________________________                                        Non-Sterile                                                                             3.52       94    84    82  74                                       Sterile   3.12       91    79    72  57                                       ______________________________________                                    

GENERATION OF ABSORPTION DATA

Under aseptic conditions, two 2-centimeter segments of a suture sampleare implanted into the left and right gluteal muscles of femaleLong-Evans rats. Two rats per period are implanted for each of theexamination periods. The animals utilized in these studies are handledand maintained in accordance with the requirements for the AnimalLaboratory Welfare Act and its 1970 Amendment. The rats are killed atthe appropriate periods by carbon dioxide asphyxiation, then theirgluteal muscles are excised and fixed in buffered formalin. Utilizingstandard histologic techniques, H and E stained slides of the musclesand implanted sutures are prepared for microscopic examination.Utilizing an ocular micrometer, the approximate suture cross-sectionalarea is estimated in each site. The cross-sectional area at five days isused as the reference value for estimating percent cross-sectional arearemaining at subsequent intervals.

EXAMPLE 27

The absorption profiles of gamma radiation sterilized suture material ofExamples 20, 21, 22, 23, and 25 were determined; results are presentedin Table VIII below:

                  TABLE VIII                                                      ______________________________________                                        Median Percent Suture Area Remaining After                                    Intramusculer Implantation in Rats*                                                  Days Postimplantation                                                  SAMPLE   5      91     119  150  154  180  182  210                           ______________________________________                                        EXAMPLE  100    --     --   28   --   1    --   0                             20                                                                            EXAMPLE  100    --     --   --   3    --   0    0                             21                                                                            EXAMPLE  100    --     --   --   0    --   0    --                            22                                                                            EXAMPLE  100    --     --   --   0    --   0    --                            23                                                                            EXAMPLE  100    100    87        0                                            25                                                                            ______________________________________                                         *The data represent the median of 7-8 cross sections in 2 rats per period     per sample.                                                              

EXAMPLE 28

The copolyester of Example 18 is made into monofilament suture materialin accordance with the following extrusion, drawing, and annealingconditions:

EXTRUSION

The copolyester was spun at 150° C. at a shear rate of 213 sec⁻¹ usingan INSTRON Capillary Rheometer with a 40 mil die (1/D=24.1) and a ramspeed of 2 cm/min. An apparent melt viscosity of 8058 poise wasobserved. The fiber was taken up at 24 feet/minute after an ice waterquench; the wound fiber was dried and subsequently drawn the same day.

DRAWING

The extrudate (diameter range 18.0 to 20.0 mils) was drawn in two stagesemploying a glycerine draw bath under the conditions of 4× at 49° C.followed by 1.50× at 78° C. and subsequently water-washed and dried invacuo at room temperature.

ANNEALING

The drawn monofilament was annealed at 80° C. for 6 hours with 5%relaxation.

EXAMPLE 29

The copolyester of Example 19 is made into monofilament suture materialin accordance with the following extrusion, drawing, and annealingconditions:

EXTRUSION

The copolyester was spun at 155° C. at a shear rate of 213 sec⁻¹ usingan INSTRON Capillary Rheometer with a 40 mil die (L/D=24.1) and a ramspeed of 2 cm/min. An apparent melt viscosity of 7789 poise wasobserved. The fiber was taken up at 24 feet/minute after an ice waterquench; the wound fiber was dried and subsequently drawn on the 14thday.

DRAWING

The extrudate (diameter range: 20.0 to 22.0 mils) was drawn in twostages employing a glycerine draw bath under the conditions of 5× at 60°C. followed by 1.2× at 80° C. and subsequently water-washed and dried invacuo at room temperature.

ANNEALING

The drawn monofilament was annealed at 80° C. for 6 hours with 5%relaxation.

The annealed monofilaments of Examples 29 and 30 were cut to appropriatelengths, placed in individual paper folders and heat-sealable ventedfoil envelopes. The packages were subjected to 50° C. and 0.1 mm Hgpressure for 72 hours to dry and subsequently sealed under nitrogen.Portions of the packaged fibers were sterilized by exposure to 2.5 Mradsof gamma radiation from a Co⁶⁰ source. Properties of the packagedmonofilaments, both sterile and non-sterile, are displayed below inTable IX:

                  TABLE IX                                                        ______________________________________                                                       Straight  Knot    Young's                                            Diam.,   Tensile ×                                                                         Tensile ×                                                                       Mod., ×                                                                         Elong.,                              Sample                                                                              Mils     10.sup.-3, psi                                                                          10.sup.-3, psi                                                                        10.sup.-3, psi                                                                        %                                    ______________________________________                                        Before Co.sup.60 Irradiation                                                  Ex. 28                                                                              7.5      84.7      60.2    153     51                                   Ex. 29                                                                              8.2      59.3      50.9    191     60                                   After Co.sup.60 Irradiation                                                   Ex. 28                                                                              7.7      69.2      49.5    144     53                                   Ex. 29                                                                              8.0      54.0      50.0    189     55                                   ______________________________________                                    

A preferred utility of the copolyesters of the invention is thepreparation of absorbable surgical filaments such as sutures andligatures.

This utility has been illustrated in detail above. The utility of thesurgical filaments of the invention is enhanced because said filamentscan be sterilized by gamma radiation and still retain a useful level ofphysical properties, and because said filaments have a highly desirablecombination of properties. One particularly interesting propertyexhibited by the subject filaments is relatively low Young's modulus,e.g., below 300,000 psi, which is an indication of good compliance,combined with acceptable straight tensile strength, e.g., above 40,000psi. For instance, see the data presented in Table IV, above, in whichfilaments made from the subject copolyesters are compared with filamentsmade from p-dioxanone homopolymers. It has also been found that thecopolyesters of the invention, in the form of surgical filaments,exhibit minimal tissue reaction after implantation in vivo. This is ahighly desirable property of a material designed to be used as anabsorbable surgical device.

While surgical filaments such as sutures and ligatures is the preferredutility for the subject copolyesters, other surgical devices can befabricated from the copolyesters. Illustrative are absorbable films,membranes, fabrics, composites, and the like.

What is claimed is:
 1. A sterile surgical suture comprising a drawn andoriented absorbable, radiation sterilizable, normally solid polymercomprising a copolyester that comprises repeating divalent units of theformulas:(A) O--CO--CH₂ --O--CH₂ CH₂, and (B) G, and (C) O--COCHR--O_(m)Ph--O--CHR--CO--Owherein G represents the residue after removal of thehydroxyl groups of a dihydric alcohol, wherein Ph represents 1,2-, 1,3-,or 1,4- phenylene or alkyl- or alkoxy-substituted phenylene, wherein mrepresents a number having a value of 0 or 1, wherein each Rindividually represents hydrogen or lower alkyl, and wherein thedivalent units (A), (B), and (C) are bonded to each other through estergroups contained in said units, wherein said polymer is produced byreacting p-dioxanone with a polyester comprising the repeating divalentunits (B) and (C) as defined above.
 2. The suture of claim 1 wherein Phrepresents 1,4-phenylene.
 3. The suture of claim 1 wherein Ph represents1,3-phenylene.
 4. The suture of claim 1 wherein G representspolymethylene of from 3 to 6 carbon atoms.
 5. The suture of claim 1wherein m is zero.
 6. The suture of claim 4 wherein m is zero.
 7. Thesuture of claim 1 wherein m is one.
 8. The suture of claim 4 wherein mis one.
 9. The suture of claim 1 wherein the divalent units are of theformula: ##STR8##
 10. The suture of claim 1 wherein the divalent unitsare of the formula: ##STR9##
 11. The suture of claim 1 wherein thedivalent units are of the formula: ##STR10##
 12. The suture of claim 1wherein the divalent units (A) constitute from about 59 to about 99weight percent of the copolyester.
 13. The suture of claim 1 wherein thedivalent units (A) constitute from about 75 to about 90 weight percentof the copolyester.
 14. The suture of claim 1 having a needle attachedto at least one end of the suture.
 15. The sterile surgical suture ofclaim 1 having a Young's modulus below about 300,000 psi.
 16. Thesterile surgical suture of claim 2 having a Young's modulus below about300,000 psi.
 17. The sterile surgical suture of claim 3 having a Young'smodulus below about 300,000 psi.
 18. The sterile surgical suture ofclaim 4 having a Young's modulus below about 300,000 psi.
 19. Thesterile surgical suture of claim 5 having a Young's modulus below about300,000 psi.
 20. The sterile surgical suture of claim 6 having a Young'smodulus below about 300,000 psi.
 21. The sterile surgical suture ofclaim 7 having a Young's modulus below about 300,000 psi.
 22. Thesterile surgical suture of claim 8 having a Young's modulus below about300,000 psi.
 23. The sterile surgical suture of claim 9 having a Young'smodulus below about 300,000 psi.
 24. The sterile surgical suture ofclaim 10 having a Young's modulus below about 300,000 psi.
 25. Thesterile surgical suture of claim 11 having a Young's modulus below about300,000 psi.
 26. The sterile surgical suture of claim 12 having aYoung's modulus below about 300,000 psi.
 27. The sterile surgical sutureof claim 13 having a Young's modulus below about 300,000 psi.
 28. Asurgical device comprising an absorbable, radiation sterilizable,normally solid polymer comprising a copolyester that comprises repeatingdivalent units of the formulas:(A) O--CO--CH₂ --O--CH₂ --CH₂, and (B) G,and (C) O--COCHR--O_(m) Ph--O--CHR--CO--Owherein G represents theresidue after removal of the hydroxyl groups of a dihydric alcohol,wherein Ph represents 1,2-, 1,3-, or 1,4- phenylene or alkyl- oralkoxy-substituted phenylene, wherein m represents a number having avalue of 0 or 1, wherein each R individually represents hydrogen orlower alkyl, and wherein the divalent units (A), (B), and (C) are bondedto each other through ester groups contained in said units, wherein saidpolymer is produced by reacting p-dioxanone with a polyester comprisingthe repeating divalent units (B) and (C) as defined above.